Ontology highlight
ABSTRACT:
PROVIDER: PRJNA721596 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14227021.fastq.gz | Fastqsanger.gz | |||
| SRR14227022.fastq.gz | Fastqsanger.gz | |||
| SRR14227023.fastq.gz | Fastqsanger.gz | |||
| SRR14227024.fastq.gz | Fastqsanger.gz | |||
| SRR14227025.fastq.gz | Fastqsanger.gz |
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Project description:Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition:Sequencing Data
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Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE204900 | GEO
Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
2022-07-14 | GSE204897 | GEO
Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an /-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIF levels and FIH catalysis regulates HIF activity. How differences in HIF hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.
2016-10-25 | E-MTAB-4264 | biostudies-arrayexpress
Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an α/β-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIFα levels and FIH catalysis regulates HIF activity. How differences in HIFα hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.
2016-08-31 | E-MTAB-4300 | biostudies-arrayexpress
Project description:ATAC sequencing of primary human monocytes cultured with and without hypoxia-mimetic agent DMOG (Dimethyloxalylglycine). Monocytes isolated from PBMCs of 7 healthy donors were cultured with and without DMOG for 24hrs and harvested at 0, 2, 10 or 24hrs for RNA sequencing. DMOG suppresses HIF Prolyl hydroxylase (HIF-PH) activity by acting as a small molecule competitive inhibitor. HIF-PH inhibition leads to increase in endogenous HIF protein levels and mimics aspects of hypoxia. This ATAC-seq study allows analysis of genome-wide changes to chromatin accessibility due to DMOG treatment.
2022-04-13 | GSE165997 | GEO
Project description:Molidustat is an inhibitor of prolyl hydroxylase that activates the hypoxia response pathway. We analyzed the transcriptome of liver cells treated with this drug and the consequences on metabolic reprogramming.
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Project description:Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction on solid cancers, by glucose transporter blocking or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are not known. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) cells induces de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (aKG), leading to attenuated activity of aKG-dependent histone demethylases and consequent histone hypermethylation. We further show that this de-differentiated and aggressive phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1a (HIF1a). Finally, we identified an HIF1a-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies targeting glucose uptake and glycolysis.
2023-04-12 | E-MTAB-11678 | biostudies-arrayexpress
Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
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Project description:Longstanding observations that fetal hemoglobin (HbF, a2g2) expression is reactivated in postnatal red blood cells (RBCs) during hypoxia or recovery from anemia remain unexplained. We identified the hypoxia inducible factor (HIF) signaling pathway as a direct regulator of HbF expression in a CRISPR/Cas9 genetic screen. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ligase stabilized its ubiquitination target HIF1a to induce g-globin gene transcription. Mechanistically, HIF1a-HIF1bheterodimers bound cognate DNA elements in BGLT3, a long-noncoding RNA gene located 2.7 kb downstream of the tandem g-globin genes. This was followed by recruitment of transcriptional activators, chromatin opening, and increased long-range interactions between the g-globin genes and their upstream enhancer. These effects were recapitulated by hypoxia or inhibition of prolyl hydroxylase domain (PHD) enzymes that target HIF1a for ubiquitination. Our findings link globin gene regulation with canonical hypoxia adaptation, elucidate a mechanism for HbF induction during stress erythropoiesis, and identify a novel therapeutic approach for β-hemoglobinopathies.
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